Overview: What every practitioner needs to knowAre you sure your patient has fragile X syndrome? What are the typical findings for this disease?

Fragile X syndrome (FXS) is the most common inherited disorder causing mental retardation. It results from a trinucleotide repeat expansion on the X chromosome. As an X-linked condition, affected male individuals (who have only one X chromosome) typically present with the characteristic moderate intellectual disability, whereas female individuals (with two X chromosomes) usually have normal intelligence or mild intellectual disability.

Physical features of FXS can be subtle and develop over time. Facial features can include a long narrow face, prominent jaw, and large ears. Macroorchidism is common in adolescents and adults, but testes size may be normal in prepubertal boys. Macrocephaly is common.

Behavioral problems are frequent in affected male patients and include hyperactivity, distractibility, anxiety, and obsessive-compulsive behaviors. Autistic-like behaviors such as hand-flapping, poor eye contact, and lack of social interest is present in up to 50% of male individuals with FXS. In fact, 2%-6% of persons with autism have FXS. Female individuals with a full mutation are more likely to have emotional problems and social avoidance than are those in the general population.

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Other occasional health issues include seizures, strabismus, gastrointestinal reflux, and recurrent otitis media. Some affected individuals have connective tissue abnormalities, including joint laxity, congenital hip dislocation, scoliosis, and aortic root dilatation. Because FXS is an X-linked condition, the mothers of boys with molecularly diagnosed FXS should be tested to determine repeat size. Recurrence risk for a premutation or full mutation carrier is up to 50% for subsequent pregnancies. Additionally, premutation carriers are at increased risk for mild learning or behavioral problems, premature ovarian insufficiency (POI), and/or fragile X-associated tremor ataxia syndrome (FXTAS).

Any patient with developmental delay, intellectual disability, or autism should have molecular testing for FXS to determine trinucleotide repeat size in the FMR1 gene. In individuals with greater than 200 repeats, the FMR1 gene is silenced and does not produce appropriate amounts of the FMRP protein. A premutation is present in those with 55-200 repeats. This allele produces FMRP but sometimes not in normal quantities, giving some mild phenotypic features of FXS, premature ovarian failure, and FXTAS. Repeats from 45-54 are in the “gray zone,” and less than repeats is in the normal range.

Common features include the following:

Intellectual disability (moderate in male individuals, normal to mild in female individuals), autistic features, macrocephaly

Macroorchidism, characteristic facial features such as long narrow face, prominent jaw, and large ears

What other disease/condition shares some of these symptoms?

Intellectual disability is a feature of multiple conditions, and FXS has few specific distinguishing characteristics. In addition to molecular testing for FXS, individuals with intellectual disability should also have a chromosomal microarray to test for small deletions/duplications on chromosomes, biochemical testing for possible metabolic causes that may be treatable, and other appropriate single-gene tests.

Occasionally, individuals with FXS have hyperphagia, mimicking Prader-Willi syndrome. Thus FXS testing should be performed when Prader-Willi syndrome has been considered and ruled out in a patient with developmental delay and obesity.

What caused this disease to develop at this time?

FXS is due to a trinucleotide repeat expansion of CGG in the FMR1 gene on the X chromosome. A full expansion of 200 or more repeats causes the gene to be hypermethylated and not expressed; thus the FMR protein is not made in sufficient quantities. The FMR protein is important in protein synthesis in the dendrites of neurons; thus the brain does not function correctly in patients with FXS.

Individuals with 55-200 repeats have a premutation that is unstable during meosis in female patients and can predispose to an expansion leading to a full mutation in offspring. The risk for expansion to a full mutation is positively correlated with repeat size (i.e. 59-69 repeats carries a 37% risk for expansion to a full mutation whereas >100 repeats carries a 100% chance of expansion).

Women with a premutation have up to a 50% chance of having a child with a full mutation (FXS in a male child and possible FXS features in a female child, depending on X inactivation levels). Additionally, female individuals with a premutation are at an increased risk (around 20%) for premature ovarian insufficiency. Male and female individuals with a premutation are also at increased risk for FXTAS; this risk increases with age. Male individuals older than the age of 50 years with a premutation have a 45% risk of FXTAS, whereas the risk for female individuals is less than 20%.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Southern blot analysis can be used to determine a low-resolution estimate of the CGG repeat number in the FMR1 gene to determine normal, premutation, or full mutation length and can measure methylation status. Polymerase chain reaction can be used to determine more specific repeat length in the normal and premutation range but can fail to amplify full mutations or large premutations. Sensitivity for these tests is around 99%. Sequencing of the
FMR1 gene as well as deletion/duplication testing may detect point mutations or copy number changes occurring in less than 1% of cases.

Would imaging studies be helpful? If so, which ones?

At birth, skeletal radiographs may be useful if there is concern for congenital hip dislocation. An echocardiogram may be warranted in childhood to examine for mitral valve prolapse or aortic root dilatation.

Confirming the diagnosis

Molecular genetic testing for FXS should be performed in the following circumstances:

Any child with developmental delay or intellectual disability of unknown cause or any child with autism

Female individuals with premature ovarian insufficiency

Male and female individuals older than 50 years of age with progressive cerebellar ataxia and intention tremor

Patients with a family history of FXS

This testing should be performed because of the prevalence of fragile X full mutations and premutations in the general population and the recurrence risk for family members of affected individuals. An algorithm has been developed by the Committee on Genetics, Health Supervision for Children with Fragile X Syndrome, 2010.

If you are able to confirm that the patient has fragile X syndrome, what treatment should be initiated?

There is no specific treatment for the cognitive effects of FXS. Early intervention—including physical, occupational, and speech therapies—should be initiated as early as possible to maximize the developmental potential of the child. Psychopharmaceutical therapy may be beneficial for behavioral aspects of the condition, including attention deficit hyperactivity disorder, obsessive-compulsive disorder, or anxiety symptoms.

Physical symptoms such as the occasional instance of seizures or strabismus should be treated as needed.

Support groups such as the Fragile X Foundation (www.fragilex.org) are available to help families with a new diagnosis and ongoing management. The family should be referred to genetic counseling to learn more about the disorder and its natural history, find support, and discuss recurrence risk and testing options.

What are the possible outcomes of fragile X syndrome?

FXS typically causes moderate intellectual disability in male individuals and normal to mild intellectual disability in female individuals. Affected patients often have behavioral problems as discussed above. Autistic behaviors are very common in male individuals with FXS. Physical manifestations can include specific facial features, macroorchidism, and tall stature in childhood that normalizes over time. Occasional health problems can include seizures, strabismus, and recurrent ear infections. Differences in connective tissue are often seen, causing joint laxity, scoliosis, and aortic root dilatation.

What causes this disease and how frequent is it?

FXS is the most common cause of inherited intellectual disability. The prevalence of FXS causing intellectual disability in the general population is around 16-25/100,000. The incidence of a full mutation is thought to be around 1/5000.

FXS is caused by an expansion of a CGG trinucleotide repeat in the FMR1 gene on the X chromosome. FMR1 codes for the FMRP protein, which plays a role in neuron development. Individuals with more than 200 CGG repeats have a full mutation, which methylates FMR1 and silences it; thus the FMRP protein is not made in sufficient quantity.

Increasing repeat size to more than 200 does not cause more severe disease because the gene is already inactivated. Male individuals have only one X chromosome and therefore only one copy of
FMR1. Lack of FMRP protein causes moderate intellectual disability. Female individuals have two X chromosomes; therefore carriers of a full mutation still make some FMRP protein and thus are less severely affected. The degree of affectedness is highly dependent on which X is inactivated in each cell in female individuals; in those with more of the abnormal
FMR1 gene active, the phenotype is presumably less severe.

Are additional laboratory studies available; even some that are not widely available?

There are no additional studies that would help diagnose FXS.

How can Fragile X synrome be prevented?

There is no prevention for FXS. When a child is diagnosed with FXS, his/her mother and other adult at-risk relatives should be offered genetic counseling to test for carrier status. Testing asymptomatic minor children for carrier status is not recommended. Once of appropriate age, they can make an autonomous decision about carrier testing.

Women who are carriers of a premutation have up to a 50% chance of passing on the abnormal
FMR1 allele. Increasing premutation size increases the chance of expansion to a full mutation during meiosis. Prenatal genetic testing is available for carriers of a premutation (or full mutation) by chorionic villus sampling or amniocentesis. Either test can directly measure CGG repeat number at close to 100% accuracy. However, both tests involve a small risk of miscarriage of around 1/ 200-1/400.

What is the evidence?

Hersh, J, Saul, R. “Committee on Genetics. Health supervision for children with fragile X syndrome”. Pediatrics. vol. 127. 2011. pp. 994-1006. (Experts in the field developed health care guidelines for the diagnosis and management of children with FXS and their families.)

Hersh, J, Saul, R. “-related disorders”. GeneReviews. Accessed December 22, 2011 at . (Summary of the clinical features, testing options, and genetic counseling for FXS- and FMR1-associated abnormalities written by experts in FXS.)